(a) Field of the Invention
The present invention relates to a method of providing myocardial protection in a patient during ischemia and reperfusion, utilizing a benzothiazepine derivative.
(b) Description of Prior Art
Timely reperfusion of ischemic myocardium limits infarct size in the experimental animal, and clinical data collected over the past decade with thrombolytic therapy have documented the benefits of early reperfusion on myocardial damage, ventricular function and mortality in patients with acute myocardial infarction (1,2).
Myocardial salvage can however be compromised by such complications as coronary reocclusion and severe residual coronary stenosis (11). Furthermore, results of animal studies and clinical investigations have provided convincing evidences that even when vessel patency is achieved, damage still proceeds in the post-ischemic myocardium (3,4). Although it is not yet unequivocally established that reperfusion can damage normal tissue, studies have shown that reperfusion not only accelerates death of irreversibly injured myocardium, but may also compromise survival of jeopardized, but still viable myocytes salvaged by reperfusion. These so-called reperfusion injuries may represent more than 50% of ultimate infarct size (5). Development of adjuvant treatments to protect the post-ischemic myocardium and maximize benefits of coronary reperfusion has thus become a major target of modern cardiovascular research.
With tissue reoxygenation, calcium-dependent mechanisms can mediate tissue damage through generation of oxygen derived radicals. A significant source of free radicals is the neutrophil which also releases lysosomal enzymes mediating cell destruction and vessel damage. Neutrophils and platelets accumulate in the reperfused territory and particularly at the edge of the infarct and the salvaged myocardium (5, 8, 11). These inflammatory cells accumulate at the wrong place and at the wrong time compromising recovery of reversibly injured myocardium salvaged by early reperfusion.
In the past years, it has been demonstrated that some benzothiazepine calcium antagonists given at the time of reperfusion, at therapeutic doses, after coronary occlusion, protect the reperfused myocardium, reducing infarct size permanently by more than 40% (6-8).
These conditions and observations could not be met or reproduced by some other calcium antagonists, suggesting that additional effects than blockade of slow-L calcium channels is likely involved in the protective mechanism. The cardio-protection was observed at dosages having no effect on cardiac work load, as estimated by the .pressure rate product, and was accompanied by improvement of the no-reflow or the circulatory failure developing in the reperfused ischemic myocardium, at doses having no measurable direct coronary vasodilating effects. Finally, it was demonstrated that these agents were preventing neutrophil accumulation in the post-ischemic myocardium.
The results led to the conclusion that some calcium antagonists could be useful in patients with acute myocardial infarction undergoing thrombolytic therapy. However, recent clinical trials have documented the risks and benefits of calcium antagonists in post-myocardial infarction patients (9, 10). Those acting on afterload are not recommended and others like diltiazem offer protection against reinfarction only in subgroups of patients. Considering the above data, Applicant searched for benzothiazepine derivatives with cardioprotective effects and possessing no cardiodepressive nor hypotensive effects that could limit their use in the set up of acute myocardial infarction and thrombolytic therapy.
It is an object of the present invention to provide a substance which can reduce infarct size at doses having no significant direct vasoactive action.
It is another object of the present invention to provide a method of ensuring myocardial protection in a patient during ischemia and reperfusion.